EP3890771A1 - Verfahren zur verminderung der konzentration des neuronalen mikrotubulus-bindenden proteins tau - Google Patents

Verfahren zur verminderung der konzentration des neuronalen mikrotubulus-bindenden proteins tau

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Publication number
EP3890771A1
EP3890771A1 EP19893894.6A EP19893894A EP3890771A1 EP 3890771 A1 EP3890771 A1 EP 3890771A1 EP 19893894 A EP19893894 A EP 19893894A EP 3890771 A1 EP3890771 A1 EP 3890771A1
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EP
European Patent Office
Prior art keywords
numb
tau
ptb
long
activity
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Pending
Application number
EP19893894.6A
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English (en)
French (fr)
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EP3890771A4 (de
Inventor
Michel CAYOUETTE
Marine LACOMME
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Adaerata LP
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Adaerata LP
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    • A01K2217/00—Genetically modified animals
    • A01K2217/20—Animal model comprising regulated expression system
    • A01K2217/203—Animal model comprising inducible/conditional expression system, e.g. hormones, tet
    • A—HUMAN NECESSITIES
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    • C12N2750/14141—Use of virus, viral particle or viral elements as a vector
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Definitions

  • a composition comprising (a) an agent that increases neuronal long phosphotyrosine-binding (PTB) Numb isoform expression and/or activity; and (b) (i) a pharmaceutically acceptable carrier; (ii) at least one further therapeutic agent; or (iii) a combination of (i) and (ii).
  • PTB neuronal long phosphotyrosine-binding
  • the fl/+ refer to one floxed allele and one wildtype allele of Numb: these animals are Numb heterozygotes when Cre is present and used as controls, whereas the fl/fl have both alleles of Numb floxed: they are Numb homozygotes knockout when Cre is present (cKO).
  • the numbers of positive cells were counted on a 200um stretch of retina.
  • the number of bipolar, amacrine and RGCs were unchanged at 5-month-old.
  • Mean ⁇ SEM, n 4 animals/genotype/time point. Anova test n.s: not significant.
  • FIGs. 6A-I Isoform Numb-72 interacts with Tau and regulates Tau level.
  • FIG. 6A Schematic of 4 Numb isoforms, differing with the presence or the absence of an insertion (arrowhead) in PTB domain arrowhead, and the presence or the absence of an insertion in the proline-rich region (PRR).
  • FIG. 6B Coimmunoprecipitation of Tau and 4 isoforms of Numb in HEK293 cells. Each Numb isoform was transfected in HEK293T cells together with a flag-tagged version of Tau and immunoprecipitation was perform 24 hours later with a flag antibody and blotted for Numb.
  • FIGs. 9A-B Numb72 stimulates secretion of the monomeric form of Tau in the extracellular media in cell lines, but not oligomeric (toxic) Tau.
  • FIG. 9A Dot blot of monomeric Tau levels (5A6) and oligomer of Tau (T22) in the media of HEK293T stable inducible cells line expressing Tau transfected with either GFP (Control) or Numb72. Tau expression was activated by adding Doxycycline 6h after transfection and the media collected 24h later for Dot-blot.
  • FIGs. 10A-H Numb72 reduces blebbing in AD mouse model RGCs.
  • FIG.10A Primary retinal cultures were performed at P8 and cells were transfected using an AmaxaTM electroporator and analysed 14 days later. Cells GFP and NF165 positive were analysed in B6129J mouse line (Control) and triple transgenic mice (3xTGAD) expressing three mutations associated with familial Alzheimer's disease (APP Swedish, MAPT P301 L, and PSEN1 M146V) after transfection of GFP or Numb-72 IRES::GFP. An increase in number of blebs (indicated by arrowheads), was observed in transgenic neuron compare to control but reversed when Numb- 72 was overexpressed. FIGs. 10B-D.
  • FIGs. 17A-D human Numb2 (Numb-66) amino acid sequence (SEQ ID NO: 3); and human Numbl nucleic acid sequence (SEQ ID NO: 5) (FIGs. 17A and C-D); and the PTB Numb domain with bolded and underlined exon 3 encoded domain (FIG. 17B) (SEQ ID NO: 4).
  • the 65kDA (Numb-65), 66kDa (Numb-66), 71 kDa (Numb-71) and 72kDa (Numb-72) correspond respectively to the isoforms 4 (e.g., accession number NP_001005745.1 or AAD54282.1 , 592aa), 2 (e.g., accession number NP_001307043.1 or NP_001005744.1 or AAD54280.1 , 603aa), 3 (e.g., accession number NP_003735.3 or AAD54281.1 , 640aa) and 1 (e.g., accession number NP_001005743.1 or AAD54279.1 , 651 aa) of Numb.
  • 2 e.g., accession number NP_001307043.1 or NP_001005744.1 or AAD54280.1 , 603aa
  • RNA binding proteins can block or promote the inclusion of specific exons by binding the same sequence at different regions of the pre-mRNA.
  • Rbfox protein can function as an activator and a repressor of alternative splicing depending on its binding location on pre-mRNA relative to the regulated exon.
  • Rbfox proteins enhance exon inclusion by binding to the (U)GCAUG element that lies downstream of the alternative Numb E9, whereas they repress inclusion by binding to the same element upstream of the alternative Numb E9 (Kim et al., 2013).
  • An ASO targeting the upstream intronic (UGCAUG) site of Numb E9 is expected to have the effect of promoting exon 9 inclusion.
  • the above-mentioned nucleic acid or vector may be delivered to cells in vivo (to induce the expression of the above-mentioned agents (e.g., a long PTB Numb isoform) using methods well known in the art such as direct injection of DNA, receptor-mediated DNA uptake, viral-mediated transfection or non-viral transfection and lipid based transfection, all of which may involve the use of gene therapy vectors.
  • Direct injection has been used to introduce naked DNA into cells in vivo.
  • a delivery apparatus e.g., a "gene gun" for injecting DNA into cells in vivo may be used.
  • Such an apparatus may be commercially available (e.g., from BioRad).
  • long PTB Numb isoform expression and/or activity could be achieved directly or indirectly by various mechanisms, which among others could act at the level of (i) transcription, for example by activating promoter or enhancer elements and thereby increasing their messenger RNA expression (e.g., by cytokine stimulation, etc.), (ii) splicing, for example by inhibiting expression or activity of a splicing regulator that promotes Numb exon 3 exclusion, or by activating a splicing regulator that enhance exon 3 inclusion, (iii) translation, (iv) post-translational modifications, e.g., glycosylation, sulfation, phosphorylation, ubiquitination (e.g., polyubiquitinylation and proteasomal degradation), (v) cellular localization (e.g., cytoplasmic versus nuclear localization), and (vi) protein-protein interaction.
  • transcription for example by activating promoter or enhancer elements and thereby increasing their messenger RNA expression (e.g., by
  • the present invention also provides a method (e.g., an in vitro method) for determining whether a test compound is useful for the prevention and/or treatment of a pathological condition associated with intraneuronal Tau accumulation, said method comprising: (a) contacting said test compound with a (neuronal) cell expressing a long PTB Numb isoform (e.g., Numb-72); and (b) determining the a long PTB Numb isoform levels in the presence or absence of said test compound; wherein an increase in the long PTB Numb isoform levels in the presence of said test compound relative to the absence thereof is indicative that said test compound may be used for the prevention and/or treatment of a pathological condition associated with intraneuronal Tau accumulation (e.g., tauopathy and/or Tau-associated optic neuropathy).
  • a pathological condition associated with intraneuronal Tau accumulation e.g., tauopathy and/or Tau-associated optic neuropathy
  • the invention further relates to methods for the identification and characterization of compounds capable of modulating long PTB Numb isoform (e.g., Numb-72) gene expression.
  • a method may comprise assaying long PTB Numb isoform (e.g., Numb-72) gene expression in the presence versus the absence of a test compound.
  • gene expression may be measured by detection of the corresponding RNA or protein, or via the use of a suitable reporter construct comprising one or more transcriptional regulatory element(s) normally associated with a long PTB Numb isoform (e.g., Numb-72) gene, operably-linked to a reporter gene.
  • the dose of the at least one agent administered to increase a long PTB Numb isoform expression and/or activity is adjusted to the level of the long PTB Numb isoform in the sample (e.g., neuronal tissue).
  • RGCs media is Neurobasal medium supplement with Sato solution, B27 supplement for Primary Neurons (Invitrogen cat# 17504044), Penicillin/Streptavidin, Sodium Pyruvate, GlutaMAXTM, N-Acetyl-Cysteine (NAC), T3 (Triiodo- Thyronine), Insulin and growth factor, BDNF and CNTF.

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EP19893894.6A 2018-12-05 2019-12-05 Verfahren zur verminderung der konzentration des neuronalen mikrotubulus-bindenden proteins tau Pending EP3890771A4 (de)

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US201862775520P 2018-12-05 2018-12-05
PCT/CA2019/051751 WO2020113338A1 (en) 2018-12-05 2019-12-05 Method of reducing neuronal microtubule binding protein tau (tau) levels

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EP4039801A4 (de) * 2019-08-16 2023-10-18 Center For Excellence In Brain Science And Intelligence Technology, Chinese Academy Of Sciences Verwendung von ptbp1-inhibitoren zur vorbeugung und/oderbehandlung von erkrankungen des nervensystems in zusammenhang mit funktionellem neuronalem tod
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